Treatment of infertility problems is a growing area of health care. Approximately 50,000 human in vitro fertilization (IVF) procedures are performed in the US annually. Although costs vary widely depending on drugs, testing and other laboratory fees, typical IVF charges are on the order of $10,000 per procedure, not counting travel, lost work time, and emotional costs for the patients. Additionally, in treatment of animals, the ability to control the birth of offspring is important for agricultural concerns and for preservation of endangered species.
Many approaches are being developed to resolve problems with infertility. Infertility is understood to be the inability to conceive after six to twelve months of sexual activity without the use of contraceptives, depending on the age of the persons involved. Because infertility exerts extreme physical, emotional and financial stresses on those who are unable to conceive, there is a great need for improved aids for reproduction. These aids are typically referred to as Assisted Reproductive Technologies (ART). By far the most common ART component is IVF, which has grown explosively in the two decades since it was developed. In its simplest form, IVF consists of pharmaceutical stimulation of the female's ovaries to produce a large number of follicles. Eggs surgically harvested from these follicles are then mixed in the laboratory with the male's sperm. If fertilization is successful, the embryos are incubated for a short time and then transferred back to the female. If one of these embryos implants in the uterine wall, a successful pregnancy may follow.
There are several modifications of this basic technique. For example, intracytoplasmic sperm injection (ICSI) can be used for cases of low sperm count or cases where the sperm has difficulty fertilizing the egg. Another IVF modification is Assisted Hatching (AH), a procedure in which the zona pellucida (the outer wall of the embryo) is mechanically cut or chemically etched, thereby partially exposing the embryo. In some laboratories, this procedure significantly improves implantation rates, particularly for older patients. Finally, IVF procedures can also incorporate donor tissues, including sperm, ova and embryos, for those individuals who cannot produce their own.
Despite its great successes, IVF has several significant problems. First and foremost, the procedure is unpredictable. Although the ideal result of any IVF procedure is a single, live birth, a viable pregnancy occurs in only about 30% of all procedures. Conversely, IVF may result in a pregnancy with multiple embryos. In this regard, twins and triplets pose relatively few risks beyond a single embryo pregnancy. The potential for problems, however, increases for higher order births. Selective embryo reduction is therefore often recommended for these cases which increases the psychological trauma for the parents.
Like unassisted reproduction, IVF begins with a source of sperm and ova. There is a virtually 100% certainty of obtaining these materials, using donor tissues if necessary. Next, fertilization occurs, and good IVF laboratories typically have a fertilization success rate of about 75%, using ICSI if appropriate. After a short incubation period, the resulting embryo is then introduced into the uterus, where implantation occurs. Implantation is generally the limiting factor in overall IVF success.
Implantation itself, however, consists of several steps. First, the embryo must enter the uterine cavity. In normal reproduction, without ART, the embryo descends through the fallopian tubes. The embryo then comes into contact with some point on the uterine wall. Next, the embryo and wall surfaces fuse at the contact point. The uterine wall properties then change dramatically at the implantation site, thus allowing the embryo to become fully implanted. For IVF, the embryo is carried into the uterine cavity in a solution injected from a syringe inserted through the cervical canal.
Although the implantation process appears to be simple enough, it is actually quite complicated and requires the coordination of many factors, some of which are unknown. A failure of any one of these processes prevents implantation and thus pregnancy. Furthermore, it is believed that implantation failures may indeed be the reason that only about 20% of even the most fertile couples conceive in a given month of attempting pregnancy.
Improving the implantation rate would make the IVF process more reliable, more effective and yield many benefits. Improving the effectiveness of the IVF process above its current 30% would reduce the need for repeat procedures, a critical factor considering the costs and stresses involved for the patients. Another benefit is that an improved success rate would make better use of the quite limited supply of donor ova and embryos. Improving the success rate would also further extend the supply of donor tissues by enabling some patients, particularly those who are older but otherwise healthy, to use their own tissues. Such patients would be more than willing to leave the donor program given the opportunity to have children of their own genetic basis. Yet another benefit is that by reducing the number of embryos required for a successful procedure, the incentive to overstimulate the ovaries is reduced, thereby reducing possible harmful side effects to the patient. Finally, improved implantation rates would eliminate the incentive to transfer large numbers of embryos back to the uterus, thereby preventing multiple births.
These advantages have been noted before, resulting in a variety of efforts to improve the implantation process, including both chemical and mechanical methods. The chemical techniques employ both natural and artificial compounds to improve the conditions of the embryo, the uterus, or both.
Many of these chemical efforts employ pharmaceutical modification of the uterine surface to make it more receptive to the embryo. Although these efforts are promising, there is concern that any agent strong enough to alter the properties of the uterus may also harm the embryo, thereby leading to birth defects. Another approach to improve implantation involves incubating the embryos to the blastocyst or later stages before transfer. Although this approach is promising, one European group has recently established an Internet registry to track the possibility of related birth defects. At the present time, none of these methods are effective in increasing the success at a viable pregnancy.
Mechanical means have focused on assisted hatching (AH) and tissue cultures. AH involves eroding the wall of the embryo by chemical and/or physical attack so that the embryo can expand and attach more readily, a technique particularly useful for patients over 38 years of age. Tissue cultures of uterine wall cells promise a more hospitable environment while still in vitro, with the hope that these conditions will prevail after transfer.
None of these techniques has produced much success. Thus, what is needed are compositions, methods and devices to aid in embryo transfer and implantation for in vitro fertilization.